Abstract

Background: Numerous retrospective analyses of prospective randomized clinical trials of patients treated with adjuvant tamoxifen and chemotherapy have demonstrated that the breast cancer intrinsic subtype Luminal A tumors generally have favorable early initial outcomes, while basal-like tumors are associated with a marked risk of early relapse. To determine the extended natural history of the intrinsic subtypes across two decades of follow up the PAM50 “non-commercial open source bioinformatics” qPCR assay was conducted on node negative tumors accrued through the Cooperative Breast Cancer Tissue Registry (CBCTR) from patients who did not receive systemic therapy.

Methods: Intrinsic subtype calls were obtained from 331 CBCTR cases treated with local interventions only. Tumors were classified into Luminal A (LumA), Luminal B (LumB), HER2-enriched (HER2-E) and Basal-like (BLBC), and correlated relapse-free (RFS). Patient survival and hazard rate were estimated using Kaplan-Meier plots and log-rank test. Multivariable Cox regression analyses were used to determine the significance of the intrinsic subtypes, adjusted with standard clinicopathological variables including tumor size, age at diagnosis, grade, radiation therapy treatment, centralized reviewed estrogen receptor, progesterone receptor and human epidermal growth factor 2 status measured by immunohistochemistry. Patients were diagnosed from 1978 to 1992, with a mean follow-up time of 13 years (range 0.5–31).

Results: Of the 331 tumors tested, 51% of cases were classified as LumA, 18% as LumB, 11% as HER2-E and 20% as BLBC. Although LumA was associated with the best outcome for the first 10-year of follow-up, the final number of RFS events were eventually comparable with those observed for BLBC with prolonged follow up (Table 1). In the multivariable Cox model, only BLBC tumors were associated with worse prognosis than LumA with borderline significance (Hazard ratio: 2.0 (95% CI 0.9–5), p = 0.07). BLBC had the highest hazard rates for the first 5 years (7% at first year to 5% at 5 yr), consistent with previous observations. Interestingly, in the absence of treatment, the slow growing LumA subtype had a gradual increase of hazard for an RFS event from 3% at 5 yrs to 4% at 10 yrs to 7% at 20 yrs. The hazard rates of LumA cross with those of BLBC at 10 years.

Conclusions: Basal-like breast cancers are associated with an early risk of relapse that decreases over time. In contrast, Luminal A breast cancer has a low risk of relapse at the outset but the risk of relapse increases over time and is responsible of the majority of the RFS events after 20 years of follow up. Luminal A breast cancers are therefore not truly low risk, particularly if they do not receive endocrine therapy; and may experience the consequences of inadequate treatment decades after diagnosis.